Community Practice Connections: 15th Annual International Congress on the Future of Breast Cancer PER Pulse™ Recap

PER Pulse™ Recap

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Emerging Strategies for Triple-Negative Breast Cancer

The 14th AnnualInternational Congress on the Future of Breast Cancer®, held July 22-23, 2016, featured state-of-the-art approaches to the management of patients with breast cancer, as well as emerging therapeutic paradigms. This first of 3 PER Pulse™ Recaps from the congress focuses on new agents in development for the treatment of triple-negative breast cancer (TNBC).

Molecular profiling studies have revealed that TNBC is a heterogeneous collection of subtypes, each with distinct natural histories and potential biologic targets for therapy. While cytotoxic chemotherapy remains the standard of care, there are a number of molecularly targeted approaches in the later phases of clinical development.

Because BRCA1/2-mutated breast cancers exhibit intrinsic defects in homologous recombination DNA repair, they are hypothesized to be particularly sensitive to DNA-damaging agents or therapies that target other DNA repair pathways. Poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib, niraparib, and talazoparib, which block the base excision DNA repair pathway, are being investigated in phase III trials for patients with BRCA1/2-mutated, metastatic TNBC. In the neoadjuvant setting, the combination of veliparib plus carboplatin produced superior pathologic complete response rates compared with standard chemotherapy in the TNBC subset of patients in the I-SPY 2 trial.

Another subset of TNBCs overexpress the androgen receptor (AR), and AR-targeted agents are being investigated for potential therapeutic effect. To date, modest activity has been observed with the AR inhibitors bicalutamide and enzalutamide as single agents (clinical benefit rates of 21% and 35%, respectively). Ongoing trials are further exploring these agents alone and in combination with other targeted therapies.

Several antibody-drug conjugates directed toward specific cell surface receptors also are being investigated in TNBC. These include sacituzumab govitecan (IMMU-132), which targets the TROP-2 antigen, and glembatumumab vedotin (CDX-011), which targets GPNMB.

Finally, the immune checkpoint inhibitors have stimulated significant interest, and this class of agents has the potential to be active across multiple TNBC subtypes. Phase I trials have reported objective response rates (ORRs) of approximately 19% with pembrolizumab and atezolizumab as single agents. In combination with nab-paclitaxel, atezolizumab produced an ORR of 46% as first-line therapy and 22% as second-line therapy in a phase Ib study in metastatic TNBC. Further follow-up of these trials is needed to determine the durability of these responses, and ongoing phase III trials will more rigorously investigate the potential benefit of immune checkpoint blockade in TNBC.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 14th AnnualInternational Congress on the Future of Breast Cancer®, including downloadable slides from the meeting.

The 14th AnnualInternational Congress on the Future of Breast Cancer®, 2016, featured state-of-the-art approaches to the management of patients with breast cancer, as well as emerging therapeutic paradigms. This second of 3 PER Pulse™ Recaps from the congress focuses on the revolutionary role of CDK4/6 inhibitors for the treatment of hormone receptor (HR)‒positive metastatic breast cancer (MBC).

Palbociclib was the first drug in this class to receive US Food and Drug Administration (FDA) approval. It is indicated as a first-line endocrine therapy in combination with letrozole based on the results from the randomized, phase II PALOMA-1 study, which showed a significant improvement in median progression-free survival (PFS) with the combination compared with letrozole alone (20.2 months vs 10.2 months; P = .0004) in estrogen receptor‒positive (ER+) MBC. These results were confirmed in the phase III PALOMA-2 trial, which again showed an approximate 10-month improvement in PFS with letrozole plus palbociclib versus letrozole plus placebo (24.8 months vs 14.5 months; P<.000001).

Palbociclib also has received FDA approval in combination with fulvestrant in patients with HR+ MBC that has progressed on a prior endocrine therapy. This approval was based on the results of the phase III PALOMA-3 trial, which showed that the combination of fulvestrant plus palbociclib significantly improved median PFS compared with fulvestrant plus placebo (9.5 months vs 4.6 months; P<.0001).

In March 2017, ribociclib became the second CDK4/6 inhibitor to gain FDA approval, with an indication in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for postmenopausal women with HR+/HER2-negative, advanced or metastatic breast cancer. Approval was based on results of the phase III MONALEESA-2 trial, which showed a significant increase in PFS for the combination compared with the AI alone (median not reached vs 14.7 months; P<.0001).

A third CDK4/6 inhibitor, abemaciclib, produced an objective response rate of 20% and a clinical benefit rate of 42% as a single agent in patients with ER+ MBC (median 3 prior lines of therapy) in the phase II MONARCH 1 trial. Ongoing phase III trials, MONARCH 2 and MONARCH 3, are investigating abemaciclib in combination with fulvestrant or a nonsteroidal AI, respectively. Recently, it was announced that both of these trials met their primary endpoint of improved PFS in abemaciclib-treated patients.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 14th AnnualInternational Congress on the Future of Breast Cancer®, including downloadable slides from the meeting.

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PER Pulse™ Recap

Evolving Paradigms for HER2-Positive Breast Cancer

The 14th AnnualInternational Congress on the Future of Breast Cancer®, featured state-of-the-art approaches to the management of patients with breast cancer, as well as emerging therapeutic paradigms. This third of 3 PER Pulse™ Recaps from the congress focuses on current standards and emerging agents for the treatment of HER2-positive (HER2+) breast cancer.

The current, evidence-based treatment algorithm for HER2+ metastatic breast cancer recommends the combination of trastuzumab, pertuzumab, and a taxane as first-line therapy, and T-DM1 as second-line therapy, based on results of the CLEOPATRA and EMILIA trials in first-line and previously treated patients, respectively. Both trials showed significant progression-free and overall survival benefits compared with standard-of-care therapies.

The combination of pertuzumab, trastuzumab, and docetaxel also received accelerated approval as preoperative therapy for patients with locally advanced, inflammatory, or early-stage, HER2+ breast cancers. This accelerated approval was based on results from the NeoSphere neoadjuvant trial, which showed a significant improvement in pathologic complete response rates when pertuzumab was added to the trastuzumab-docetaxel backbone (46% vs 29%; P = .0141). An ongoing phase III trial (APHINITY) is evaluating the addition of pertuzumab to trastuzumab-containing chemotherapy in the adjuvant setting.

With regard to novel agents, neratinib, an irreversible HER1/2/4 tyrosine kinase inhibitor, has been evaluated as extended adjuvant therapy in patients who completed a standard trastuzumab-containing adjuvant regimen. Two-year invasive disease-free survival was significantly improved with 1 year of neratinib compared with placebo (94% vs 92%; P =.009), and the magnitude of difference was greatest in the centrally confirmed HER2+/HR+ subgroup (97% vs 88%; P<.001). The most common grade 3/4 adverse event associated with neratinib is diarrhea, and an ongoing study is evaluating prophylactic administration of loperamide to ameliorate this side effect.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 14th AnnualInternational Congress on the Future of Breast Cancer®, including downloadable slides from the meeting.